The present invention describes a novel process for making a novel epoxide intermediate useful for making 13,14-dihydro prostaglandin A, E and F derivatives. Naturally occurring prostaglandins (PGA, PGB, PGD, PGE, PGF, and PGI) are C-20 unsaturated fatty acids. Prostaglandin A, E, and F derivatives are distinguishable as such by the substituents on the alicyclic ring. PGA derivatives are characterized by a ketone at C.sub.9 and a double bond between C.sub.10 and C.sub.11. PGE derivatives are characterized by a ketone at C.sub.9 and a hydroxyl at C.sub.11. PGF derivatives are characterized by hydroxyl groups at both C.sub.9 and at C.sub.11.
Such derivatives are useful for the treatment of many medical disorders including, for example, ocular disorders, hypertension, fertility control, and osteoporosis. For example, the prostaglandin 13,14-dihydro PGF.sub.1 .alpha., disclosed in U.S. Pat. No. 3,776,938 (1973) by Bergstrom, S., and Sjovall, J. of the Kemiska Institutionen, Karolinska Institute, Stockholm 60, Sweden has a stimulatory effect on smooth muscle contraction as shown by test strips of guinea pig ileum, rabbit duodenum, or gerbil colon. Further information regarding the biological effects of 13,14-dihydro PGA, PGE and PGF derivatives are disclosed in the following references: U.S. Pat. No. 3,882,241 issued to Pharriss, G., May 6, 1975; G.B. U.S. Pat. No. 1,456,512 (1976) issued to Pfizer Inc., Bundy, G. L.; Lincoln, F. H., "Synthesis of 17-Phenyl-18,19,20-trinor prostaglandins I. The PG1 Series", Prostaglandins Vol. 9 (1975) pp. 1-4; CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids Vol. 1, Chemical and Biochemical Aspects, Parts A & B, A. L. Willis, eds., CRC Press (1987); Liljebris, C.; et. al. "Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2.alpha. Isopropyl Ester: Potential Antiglaucoma Agents", Journal of Medicinal Chemistry Vol. 38, (1995), pp. 289-304; Collins, P. W.; Djuric, S. W. "Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs", Chemical Reviews 93 (1993), pp. 1533-1564.
In the art, 13,14 dihydro prostaglandin E derivatives have been synthesized according to several different methods. Such methods include those described in the following references: Corey et al., J. Amer. Chem. Soc. 1969, 91, p. 5675; Corey et al., J. Amer. Chem. Soc. 1970, 92, p. 397; Corey et al., J. Amer. Chem. Soc. 1970, 92, p. 2586; Corey, E. J. Ann. N.Y. Acad. Sci. 1971, 180, p. 24; Corey et al., The Logic of Chemical Synthesis, John Wiley & Sons: New York, 1989, p. 250-266.
To date, prostaglandin E derivatives have generally been assembled through the common Corey aldehyde intermediate via introduction of the omega side-chain through Wadsworth-Horner-Emmons phosphonate chemistry, reduction and protection of the C.sub.15 position, introduction of the top chain via Wittig chemistry, oxidation of the C.sub.9 position with Jones reagent, and finally, removal of the various protecting groups with the appropriate reagent(s).
Prostaglandins of the A series have generally been assembled from the PGE series by acid or base induced elimination of the C11 hydroxyl group. Methods for conversion of PGE derivatives to PGA derivatives include those described in the following references: Stork et al., J. Amer. Chem. Soc. 1976, 98, p. 1583; Stork et al., J. Amer. Chem. Soc. 1978, 100, p. 8272.
In the art, 13,14 dihydro prostaglandin F derivatives have been synthesized according to several different methods. Such methods include those described in the following references: G.B Patent No. 1,040,544 issued to A. C. Chapman; G.B. Patent No. 1,186,505 issued to the Upjohn Co.; U.S. Pat. No. 3,505,386 issued to Babcock, J. C., and Beal, P. F., III, Apr. 7, 1970, U.S. Pat. No. 3,435,053 issued to Beal, Lincoln, Jr., Portage, and Pike, Mar. 25, 1969; G.B. Patent No. 1,251,750 issued to the Upjohn Co.; Bundy, G. L.; Lincoln, F. H. "Synthesis of 17-Phenyl-18,19,20-trinorprostaglandins I. The PG.sub.1 Series" Prostaglandins, Vol. 9 (1975), pp. 1-4.
To date, the synthesis of 13,14-dihydro prostaglandin F derivatives has involved either conversion of the 13,14-dihydro prostaglandin E.sub.1 skeleton (see Sjovall, et. al., U.S. Pat. No. 3,776,938) via reduction of the carbonyl moiety at Cg (prostaglandin numbering) to the alcohol or by exhaustive hydrogenation of the preassembled PGF.sub.2 .alpha. skeleton (see for example: Bundy, G. L.; Lincoln, F. H. "Synthesis of 17-Phenyl-18,19,20-trinor prostaglandins I. The PG.sub.1 Series" Prostaglandins, Vol. 9 (1975), pp. 1-4.) The prostaglandin F.sub.2 .alpha. skeleton is prepared in a variety of ways; generally from the condensation of the Corey aldehyde (see for example: Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. "Stereo-Controlled Synthesis of Prostaglandins F.sub.2.alpha. and E.sub.2 (dl)" J. Am. Chem. Soc. 1969, 91(20), p.5675-5677] with the appropriate oxophosphonate, followed by reduction at C.sub.15 (prostaglandin numbering)(see, for example: Noyori, R,; Tomino, I.; Yamada, M.; Nishizawa, M. "Synthetic Applications of the Enantioselective Reduction by Binaphthol-Modified Lithium Aluminum Hydride Reagents" J. Amer. Chem. Soc. 1984, 106, p. 6717-6725), reduction to the lactol and addition of the C.sub.1 -C.sub.7 (prostaglandin numbering) side-chain (see, for example: G.B. Patent No. 1,456,512, complete specification published Nov. 24, 1976). For other methods to prepare the prostaglandin F.sub.2 .alpha. skeleton for conversion into the 13,14-dihydro prostaglandin F1.alpha. derivatives, see: Collins, P. W.; Djuric, S. W. "Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs", Chemical Reviews, 93, (1993), pp.1533-1564.
Synthesis of 13,14-dihydro prostaglandin A, E, and F derivatives using the methods described above is somewhat lengthy and expensive. Thus, it would be desirable to have a method that is higher yielding, more economical, and that involves fewer steps for preparing 13,14-dihydro prostaglandin A, E, and F derivatives.